Epigenetic inhibition of the tumor suppressor ARHI by light at night‐induced circadian melatonin disruption mediates STAT3‐driven paclitaxel resistance in breast cancer

Abstract

Disruption of circadian time structure and suppression of circadian nocturnal melatonin (MLT) production by exposure to dim light at night (dLAN), as occurs with night shift work and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of breast cancer and resistance to tamoxifen and doxorubicin. Melatonin inhibition of human breast cancer chemoresistance involves mechanisms including suppression of tumor metabolism and inhibition of kinases and transcription factors which are often activated in drug-resistant breast cancer. Signal transducer and activator of transcription 3 (STAT3), frequently overexpressed and activated in paclitaxel (PTX)-resistant breast cancer, promotes the expression of DNA methyltransferase one (DNMT1) to epigenetically suppress the transcription of tumor suppressor Aplasia Ras homolog one (ARHI) which cansequester STAT3 in the cytoplasm to block PTX resistance. We demonstrate that breast tumor xenografts in rats exposed to dLAN and circadian MLT disrupted express elevated levels of phosphorylated and acetylated STAT3, increased DNMT1, but reduced sirtuin 1 (SIRT1) and ARHI. Furthermore, MLT and/or SIRT1 administration blocked/reversed interleukin 6 (IL-6)-induced acetylation of STAT3 and its methylation of ARH1 to increase ARH1 mRNA expression in MCF-7 breast cancer cells. Finally, analyses of the I-SPY 1 trial demonstrate that elevated MT 1 receptor expression is significantly correlated with pathologic complete response following neo-adjuvant therapy in breast cancer patients. This is the first study to demonstrate circadian disruption of MLT by dLAN driving intrinsic resistance to PTX via epigenetic mechanisms increasing STAT3 expression and that MLT administration can reestablish sensitivity of breast tumors to PTX and drive tumor regression. K E Y W O R D Scircadian disruption, melatonin, paclitaxel resistance, STAT-3 2 of 15 | XIANG et Al.

Role of STAT3 signaling pathway in breast cancer

“…Meanwhile, Kim et al have discovered that Oct-4 confers radiation resistance via STAT3 and NF-Bmediated IL-24 production in breast cancer cells [70]. In addition, paclitaxel is widely used as a clinical drug of breast cancer treatment, and phosphorylated STAT3 could mediate Survivin to promote paclitaxel resistance [71].…”

Truncated HDAC9 identified by integrated genome-wide screen as the key modulator for paclitaxel resistance in triple-negative breast cancer

“…In the current study, we aimed to understand the mechanisms responsible for paclitaxel resistance involving JAK/STAT3 signaling. Previous studies have reported that STAT3 activation occurs through the IL6 cytokine family 44 . Hartman and colleagues described that IL6 family members IL6 and IL8 are critical for resistance to paclitaxel, due to their stimulation of multiple pathways, including the JAK/STAT3 pathway 45 .…”

A meta‐analysis of microRNA networks regulated by melatonin in cancer: Portrait of potential candidates for breast cancer treatment

“…It has been recently reported that melatonin inhibition of human breast cancer chemoresistance is associated with mechanisms including metabolism switching, and inhibition of specific kinases and transcription factors is often activated in these drug-resistant tumors. 68 These effects seem to be mediated by its MT1 receptor and induction of ARHI protein expression. MT1 activation has also been significantly associated with a good prognosis (higher in luminal A vs. luminal B) and worse prognosis in triple-negative tumors.…”